Human infections with Neisseria gonorrhoeae are characterized by the variability of the pathogen during the course of disease. We have studied one family of outer-membrane proteins (the Opa or "opacity- related" proteins) which have been shown to be expressed in vivo during natural and human challenge infections. We have focussed on the genetic mechanisms used by the organism to vary expression of this protein family and the biological properties associated with expression. A common mechanism drives the expression state changes ("phase variation") of the opa multigene family which serves as a paradigm for other genes and gene families which utilize similar means of genetic variation. Changes in the number of short DNA repeats within the coding region of the individual genes alter their ability to be fully translated into mature proteins ("translational-frameshifting"). We have identified a number of cellular processes which influence the ability of the bacterium to control the rate of change in these repetitive sequences. Specific genes involved in these processes have been isolated from N. gonorrhoeae and their role in phase variation is being studied. The variably expressed Opa proteins have previously been described as imparting a wide variety of biological phenotypes (generally involving increased adherence to human cells). We have focussed our studies on the role of Opa protein expression in resistance to early (i.e. non-immune) host defence mechanisms. Specifically the influence of Opa protein expression on the ability of bacterial cells to resist killing by human complement (in normal human serum, NHS) and human PMNs (in the presence and absence of NHS).